FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age

García‐Prat, Laura; Perdiguero, Eusebio; Alonso-Martín, Sonia; Dell’Orso, Stefania; Ravichandran, Srikanth; Brooks, Stephen R.; Juan, Aster H.; Campanario, Silvia; Jiang, Kan; Hong, Xiaotong; Ortet, Laura; Ruiz‐Bonilla, Vanessa; Flández, Marta; Moiseeva, Victoria; Rebollo, Elena; Jardı́, Mercè; Sun, Hongwei; Musarò, Antonio; Sandri, Marco; Sol, Antonio del; Sartorelli, Vittorio; Muñoz‐Cánoves, Pura

doi:10.1038/s41556-020-00593-7

Cited by 115 publications

(101 citation statements)

References 63 publications

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“…Age-dependent transcriptome changes of MuSCs have been characterized in multiple studies; however, transcript levels can only partially predict changes at the protein level during aging due to a progressive decoupling between the transcriptome and proteome during aging (Janssens et al, 2015;Kelmer Sacramento et al, 2020;Ori et al, 2015;Wei et al, 2015). To investigate if the proteome and transcriptome are also uncoupled in aging MuSC, we re-analyzed transcriptome data from three independent studies based on microarray technology (Alonso-Martin et al, 2016;Liu et al, 2013;Lukjanenko et al, 2016;Price et al, 2014) and two recent datasets obtained by RNA sequencing (RNA-seq; García-Prat et al, 2020;Li et al, 2019). We compared age-related transcriptome and proteome changes by focusing on the 162 proteins significantly affected in both old and geriatric MuSCs (Figure 1E).…”

Section: Aging Changes the Proteome Of Muscsmentioning

confidence: 99%

Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality

et al. 2021

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Section: Aging Changes the Proteome Of Muscsmentioning

confidence: 99%

Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality

et al. 2021

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“…MuSC quiescent state is characterized by the expression of PAX7 and FOXO transcription factors [13]. Myf5 and Myod1 are also transcribed in quiescent MuSCs, but post-transcriptional regulation prevents their translation (PAX7 + FOXO + MYF5 -MYOD1 -) ( Fig.…”

Section: Muscs Mediate Regeneration Of Skeletal Musclementioning

confidence: 99%

“…Myf5 and Myod1 are also transcribed in quiescent MuSCs, but post-transcriptional regulation prevents their translation (PAX7 + FOXO + MYF5 -MYOD1 -) ( Fig. 1) [13,14]. More specifically, Myf5 mRNA is sequestered in messenger ribonucleoprotein granules (mRNPs) to avoid its translation [15] while Myod1 mRNA retains an intron that prevents its translocation out of the nucleus [16].…”

Section: Muscs Mediate Regeneration Of Skeletal Musclementioning

confidence: 99%

“…As the MuSCs start to accumulate, PAX7 and MYF5 expression becomes repressed while MYOG becomes expressed to drive cell cycle exit and form myocytes (PAX7 --FOXO -MYF5 -MYOD1 + MYOG + ) ( Fig. 1) [13,18]. Finally, the formation of multinucleated myofibers results in the decreased expression of MYOD1 while MYF6/MRF4 becomes highly expressed in the functional muscle fiber [19][20][21].…”

Section: Muscs Mediate Regeneration Of Skeletal Musclementioning

confidence: 99%

“…To maintain this balance, different pathways contribute to the quiescent MuSC transcriptional network. In particular, the expression of forkhead box (FOXO) transcription factors, FOXO1, FOXO3A, and FOXO4, were reported to be required for the maintenance of the MuSC quiescence [13]. FOXO3 maintains the expression of Notch pathway components [27].…”

Section: Quiescence and Early Activationmentioning

confidence: 99%

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Epigenetic regulation of satellite cell fate during skeletal muscle regeneration

et al. 2021

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In response to muscle injury, muscle stem cells integrate environmental cues in the damaged tissue to mediate regeneration. These environmental cues are tightly regulated to ensure expansion of muscle stem cell population to repair the damaged myofibers while allowing repopulation of the stem cell niche. These changes in muscle stem cell fate result from changes in gene expression that occur in response to cell signaling from the muscle environment.Integration of signals from the muscle environment leads to changes in gene expression through epigenetic mechanisms. Such mechanisms, including post-translational modification of chromatin and nucleosome repositioning, act to make specific gene loci more, or less, accessible to the transcriptional machinery. In youth, the muscle environment is ideally structured to allow for coordinated signaling that mediates efficient regeneration. Both age and disease alter the muscle environment such that the signaling pathways that shape the healthy muscle stem cell epigenome are altered. Altered epigenome reduces the efficiency of cell fate transitions required for muscle repair and contributes to muscle pathology. However, the reversible nature of epigenetic changes holds out potential for restoring cell fate potential to improve muscle repair in myopathies.In this review, we will describe the current knowledge of the mechanisms allowing muscle stem cell fate transitions during regeneration and how it is altered in muscle disease. In addition, we provide some examples of how epigenetics could be harnessed therapeutically to improve regeneration in various muscle pathologies.

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FOXO1 promotes the expression of canonical WNT target genes in examined basal‐like breast and glioblastoma multiforme cancer cells

Pintor,

Lopez,

Flores

et al. 2023

FEBS Open Bio

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Basal‐like breast cancer (BBC) and glioblastoma multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM have stem‐cell‐like gene expression signatures, which are in part driven by forkhead box O (FOXO) transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with AS1842856 and performed RNA sequencing. AS1842856 binds to unphosphorylated FOXO1 and inhibits its ability to directly bind to DNA. Gene Set Enrichment Analysis (GSEA) indicated that a set of WNT pathway target genes, including lymphoid enhancer‐binding factor 1 (LEF1) and transcription factor 7 (TCF7), were robustly induced after AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172 and DBTRG upon AS1842856 treatment. In contrast, follow‐up RNA interference (RNAi) targeting of FOXO1 led to reduced LEF1 and TCF7 gene expression in BT549 and U87MG cells. In agreement with RNAi experiments, CRISPR Cas9‐mediated FOXO1 disruption reduced the expression of canonical WNT genes LEF1 and TCF7 in U87MG cells. The loss of TCF7 gene expression in FOXO1 disruption mutants was restored by exogenous expression of the DNA‐binding‐deficient FOXO1‐H215R. Therefore, FOXO1 induces TCF7 in a DNA‐binding‐independent manner, similar to other published FOXO1‐activated genes such as TCF4 and hes family bHLH transcription factor 1 (HES1). Our work demonstrates that FOXO1 promotes canonical WNT gene expression in examined BBC and GBM cells, similar to results found in Drosophila melanogaster, T‐cell development and murine acute myeloid leukemia (AML) models.

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FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age

Cited by 115 publications

References 63 publications

Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality

Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality

Epigenetic regulation of satellite cell fate during skeletal muscle regeneration

FOXO1 promotes the expression of canonical WNT target genes in examined basal‐like breast and glioblastoma multiforme cancer cells

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